2-r-substituted-1,2,5-thiadiazole-3-one antimicrobials

ABSTRACT

2-R-substituted-1,2,5-thiadiazole-3-ones have broad spectrum antibacterial and antifungal activity. They are especially useful in agriculture to protect plants against diseases such as leaf, stem, and fruit spotting, internal discoloration and decay of fruits and vegetables. These compounds are particularly active against diseases caused by the genera Pseudomonas, Xanthomonas, Erwinia, and Corynebacterium.

This application is a continuation-in-part application of U.S. Ser. No.684,137 filed May 7, 1976 now abandoned.

This invention relates to a new class of antibacterial and antifungalcompounds, particularly 2-R-substituted-1,2,5-thiadiazole-3-ones.Although derivatives of 1,2,5-thiadiazoles are known, for instance, U.S.Pat. Nos. 3,854,000 and 3,763,176, such compounds must necessarily havea halogen in the 4-position. The compounds of this invention are halogenfree.

The 2-R-substituted-1,2,5-thiadiazole-3-ones of this invention have thestructural formula: ##STR1## where R is a hydrocarbon group of from 1-16carbon atoms including C₁ to C₁₆ alkyl, phenyl-C₁ to C₁₀ alkyl, andphenyl. In general, it is preferred that the hydrocarbon group R containfrom 6-14 carbon atoms, C₁₂ alkyl and benzyl being the most preferredgroups. The term "alkyl" includes straight or branched hydrocarbonradicals. R includes, for example, methyl, ethyl, propyl, isopropyl,butyl, sec-butyl, t-butyl, pentyl, 1-(2-ethyl)propyl, hexyl,1-(2,3-dimethyl)butyl, heptyl, 1-(2-ethyl-4-methyl)butyl, octyl, nonyl,decyl, dodecyl, hexadecyl, 4-t-butylphenyl, 2,4-diethylphenyl,4-ocylphenyl, 3-heptylphenyl, 4-hexylphenyl and 2,4,6-triethylphenyl.

The compounds of this invention are prepared by reacting an amide offormula II with at least one mole of sulfur monohalide, S₂ X₂, where Xis bromine or chlorine. ##STR2##

The reaction is conducted in any inert solvent such as dimethylformamideor hexamethylphosotriamide at a temperature of from about -10° to 60° C.for from about 10 to 18 hours.

The molar ratios of glycine R-substituted amide free base or salt to SX₂can range from 1:2 to 1:5 although a molar ratio of 1:3 is mostsatisfactory.

After reaction is complete, the solvent is stripped under vacuum.

The 2-R-substituted-1,2,5-thiadiazole-3-ones are neutral compoundsreadily extractable from acidic or basic mixtures.

The rather minor quantities of compound IV produced in the preparationof product III can be removed by usual techniques such as distillation,crystallization as well as column chromatography.

The following examples are presented to illustrate the invention butshould not be construed as limitations thereof.

EXAMPLE I 2-n-Dodecyl-1,2,5-thiadiazole-3-one

N-n-Dodecyl-2-aminoacetamide.HCl (23.55 g., 84.6 mmoles) is added inportions over 45 minutes to a stirred solution of sulfur monochloride(34.8 g., 258 mmoles) dimethylformamide in 75 ml. (DMF), maintaining thereaction temperature between 5°-8° C. During the addition, the mixturebecame quite thick and 25 ml. DMF is added. After the addition iscomplete, another 25 ml. DMF is added and the reaction mixture allowedto warm to room temperature and stirred for 18 hours. The reactionmixture is poured into 1 liter water and extracted three times with 300ml. ether. The ether is dried (Na₂ SO₄) and evaporated to dryness. Thesolid residue was chromatographed on silica gel to afford 18.44 g. of2-n-dodecyl-1,2,5-thiadiazole-3-one (81% yield), m.p. 68°-70° C.(hexane).

Analysis calculated for C₁₄ H₂₆ N₂ OS: C, 62.18; H, 9.69; N, 10.36; S,11.85. Found: C, 62.37; H, 9.53; N, 10.50; S, 12.00.

The above procedure is general for the preparation of the 2-C₁ to C₁₆-R-substituted-1,2,5-thiadiazole-3-ones of this invention and the entirerange of products are obtained by employing 2-C₁ to C₁₆-R-substituted-2-aminoacetamide in analogous molar quantities to theN-n-dodecyl2-aminoacetamide.

                  TABLE I                                                         ______________________________________                                                                 Product                                               REACTANTS                                                                                              ##STR3##                                            R-2-aminoacetamide   S.sub.2 X.sub.2                                                                       R                                                ______________________________________                                        H.sub.2 NCH.sub.2 CONHCH.sub.2 φ . HCl                                                         S.sub.2 Cl.sub.2                                                                      CH.sub.2 φ-H.sub.2 NCH.sub.2 CONHCH.sub.3                                  . HCl S.sub.2 Cl.sub.2 CH.sub.3                 H.sub.2 NCH.sub.2 CONH.sub.2 φ . HCl                                                           S.sub.2 Cl.sub.2                                                                      φ                                            H.sub.2 NCH.sub.2 CONH.sub.2 CH.sub.2 CH.sub.2 CH.sub.3 .                                          S.sub.2 Cl.sub.2                                                                      CH.sub.2 CH.sub.2 CH.sub.3                       H.sub.2 NCH.sub.2 CONH.sub.2 CH(CH.sub.3).sub.2                                                    S.sub.2 Cl.sub.2                                                                      CH(CH.sub.3).sub.2                               ______________________________________                                    

The N-substituted-2-aminoacetamides intermediates, required for thesynthesis of the 2-substituted-1,2,5-thiadiazole-3-ones, can be preparedby standard methods (James R. Vaughan, Jr., and Ruth L. Osato, J. Amer.Chem. Soc., 74, 676 (1952), and Miklos Bodansky and Vincent Du Vigneaud,J. Amer. Chem. Soc., 81, 5688 (1959)). The following example forN-n-dodecyl-2-aminoacetamide hydrochloride is typical.

EXAMPLE II N-n-Dodecyl-2-aminoacetamide Hydrochloride

Step A: N-Benzyloxycarbonyl glycine (209.2 g., 1 mole) is suspended in600 ml. CHCl₂ and 140 ml. triethylamine is added. A solution graduallyresults. This mechanically stirred solution is cooled in an ice-saltbath and ethyl chloroformate (110 g., 1 mole) is added dropwise over 45minutes, keeping the temperature at 0°-3° C. The resulting mixture isstirred in the cold an additional 1/2 hour. A solution of n-dodecylamine(185.4 g., 1 mole) in 250 ml. CH₂ Cl₂ is added dropwise, keeping thetemperature below 10° C. After the addition, the mixture is allowed tocome to room temperature and stirred for 20 hours; diluted with 500 ml.CH₂ Cl₂ and washed with water, then diluted NaOH, then water, dried andevaporated to dryness. The residual solid is suspended in 1 literpetroleum ether (30°-60° C.) and boiled for 15 minutes, cooled andfiltered, yielding 228.3 g. ofN-n-dodecyl-(2-benzyloxycarbonylamino)acetamide, m.p. 112°-115° C.(dec.) (benzene-petroleum ether).

Analysis calculated for C₁₂ H₃₆ N₂ O₃ : C, 70.18; H, 9.64; N, 7.44.Found: C, 69.76; H, 9.26; N, 7.56.

Step B: 10 G. of N-n-dodecyl-(2-benzyloxycarbonylamino)acetamide issuspended in 200 ml. MeOH and 1 g. 10% Pd/charcoal hydrogenated until nomore H₂ is absorbed. The resulting suspension is acidified with 3 ml.concentrated HCl and filtered. The solution is concentrated under vacuumuntil the product begins to crystallize. It is warmed to dissolve thesolid and ether added to induce crystallization. This is filtered toyield N-n-dodecyl-2-aminoacetamide hydrochloride (5 g.) as whitecrystals, m.p. 200° C.

Analysis calculated for C₁₄ H₃₀ N₂ O.HCl: C, 60.30; H, 11.21; N, 10.04;cl, 12.71. Found: C, 60.49; H, 11.27; N, 10.23; Cl, 12.94.

In an analogous manner C₁ -C₁₆ -alkylamines can be substituted for asimilar molar quantity of the n-dodecylamine to prepare the entire rangeof the compounds of this invention. Thus, substituting respectivelybenzylamine, methylamine, aniline, 2-aminopropane and 1-aminopropane forthe n-dodecylamine there is obtained N-benzyl-2-aminoacetamide . HCl;N-methyl-2-aminoacetamide . HCl; N-phenyl2-aminoacetamide . HCl;isopropyl-2-aminoacetamide . HCl; and N-propyl-2-aminoacetamide . HCl.

The compounds of our invention are broad spectrum antibacterial andantifungal agents. For use, the compounds described herein can beapplied neat or employed in a diluted form. Satisfactory diluentsinclude any inert material not destructive of the antimicrobial activityand especially liquid formulations comprising aqueous dispersions,solutions, and emulsions. Solid diluents include talc, corn starch,alumina and diatomaceous earth. The antimicrobial agents of thisinvention can also be deposed on materials such as natural fibersincluding paper, cotton, wool and synthetic fibers such as nylon,polypropylene, as well as upon inanimate surfaces including hardsurfaces such as wood, glass, metal, tile, rubber, plastic, and poroussurfaces such as concrete, leather and the like.

Another application is alone or in solution or suspension or inconjunction with soaps or detergents for use in cleansing the skin,particularly in presurgical scrubbing formulations, or in formulationsfor controlling the growth of Corynebacterium acnes. C. acnes is astrain of bacteria implicated in acne conditions, especially Acnevulgaris, wherein applications of as little as 1 to 5 ppm. is effectivein controlling such skin dwelling bacteria. Larger concentrations can beused, if desired, without irritation or discomfort such as 2500 ppm andhigher. Where the cleansing formulation is diluted with water upon use,the formulation can comprise from 0.01% by weight and more of thecompounds of this invention.

In addition, the compounds described herein can be employed in impoundedwater, such as swimming pools, ponds or industrially-used water such aspapermill water to inhibit growth of undesirable bacteria, fungi, and/oralgae at levels as low as 0.5-5 ppm.

In the control of slime-producing microorganisms and algae inrecirculating industrial waters, particularly cooling operations andespecially installations such as cooling towers, the compounds of thisinvention are usually employed alone, but can also be used incombination with other antimicrobial agents. Concentrations in therecirculating water of as little as 1 × 10⁻⁴ % by weight are effectivein inhibiting microbial growth. To insure effectiveness, especiallyagainst more resistant strains of microorganisms, and also when make-upwater is added to replace water lost by evaporation and the like,concentrations of from 1 × 10⁻⁴ % to 5 × 10⁻² % by weight are mostsatisfactory. Dosage may be continuous or as intermittent "shocktreatment", i.e., addition in a 10-20 minute period every 4-8 hours.They are especially useful against bacteria and fungi responsible forstunting the growth and even destruction of many types of crop-producingplants. In agriculture, severe problems are faced in the raising ofcotton, beans, corn and other crops because of the loss of yield peracre due to the action of soilborne fungi on seed and on the roots ofthe young plants. Control or elimination of these losses can beaccomplished by the use of the compounds herein described as soildisinfectants in accordance with the invention. They can also be usedfor the control of bacterial and fungal diseases on trees and storedcrops.

In formulating the compounds of this invention for the above uses, thesecompounds can be employed in combination with other antimicrobialagents, surfactants, insecticides, defoamers, odorants, or as chelatesof metals such as copper, calcium, magnesium and iron.

Wettable powder formulations for use as a dispersant in water representa practical means for good distribution in soil. Other methods ofachieving the same results include the preparation of dusts. All of thethiadiazole-3-ones can be blended as fine powders with the commonly usedpowder diluents such as talc, clay refined silicates, wood flour, sand,magnesium oxide, calcium carbonate, fuller's earth, kaolin, diatomaceousearth, mica, pumice and the like. The powder can have the followingformulation:

    ______________________________________                                                              Percent                                                 ______________________________________                                        R-Substituted-1,2,5-thiadiazole-3-one                                                                  1-75                                                 Inert Diluent (clay, talc, etc.)                                                                      25-99                                                 ______________________________________                                    

The mixtures may be finely powdered, e.g., to the 1-10 micron averageparticle size, or be made by blending the already finely powderedingredients.

For application as agricultural disinfectants the dusts may be appliedto the seed and surrounding soil at the time of planting. Theconcentration of the sterilant is adjusted to give an effective,nonphytotoxic dosage in the soil. In general, the soil concentrationshould be from 10 to 25 parts per million (of active ingredient). Formost economical and effective use the dusts can be applied in bands of 6to 8 inches centered on the rows just prior to seeding. The material canthen be rototilled to a depth of several inches. This mode of treatmentsaves material and protects the root system of young plants againstmicrobial attack. For the protection of a given crop, such as cabbage,the band spread of antimicrobial can vary from 8 inches for black rootdisease to 12-15 inches for club root disease prevention. Similarly, thedepth to which the fungicide should be distributed can vary from 2 to 6inches.

The wettable powders can be prepared by the addition of 0.1-5% of awetting agent to the powder blends. Many dispersing agents arecommercially available which are nonphytotoxic at the requiredconcentrations. These may, for example, be alkali metal and amine saltsof sulfated and sulfonated acids, alcohols, and oils, or polyethoxylatedalkyl phenols, long chain fatty amine quaternary salts, partial phenols,long chain fatty amine quaternary salts, partial fatty acid esters ofpolyhydric alcohols, etc. Some dispersants can be used in preparingemulsifiable concentrates of the polyamines in organic solvents. Many ofthese agents are available in solvent-soluble form. The manner ofapplication to the soil is similar to the dusts. Spray equipment is usedto spread the suspensions or emulsions over the soil and by discing, thefungicidal agents can be uniformly distributed to varying depths. Sprayapplication is also effective for band-limiting the dosages.

Other agricultural uses for these formulations involve the eradicationof bacterial blights of plants by application to the involved surfaceareas. The compounds of this invention show high orders of bacterialinhibition and are especially useful for this purpose. Some of thediseases which are of commercial importance in decreasing yield andquality and are controlled by the compositions of the invention are fireblight of apple and pear, bacterial spot on stone fruit, cherry leafspot, walnut blight, common blight of bean, bacterial spot of tomato andpepper, and potato seed piece decay. The effective concentration ofR-substituted-1,2,5-thiadiazole-3-one required varies from 5-200 partsper million parts of the material to be protected. They may be appliedas dusts, powder dispersions in water as emulsions in water, or asaqueous dipping baths. Other plant diseases which can be controlled bytreatment with these formulations are fungal in origin, such as the manykinds of powdery mildew and leaf scabs.

For seed treatment, proportions as low as 1 to 4 ounces per hundredweight (550 to 600 ppm on seed) are effective against various fungi.

The compounds of the invention can be used in form of aqueoussuspensions or emulsions, the base products being generally insoluble inwater. For this type of formulation various powdered carriers can beemployed to aid in achieving uniform distribution. Talc, fuller's earth,calcium silicate, calcium carbonate, clays and the like are admixed withthe agent along with wetting and dispersing agents and sticking agents.For maximum chemical compatability those which are non-ionic incharacter are preferred. Other nonionic or cationic surfactants are alsosatisfactory.

What is claimed is:
 1. A compound of the formula: ##STR4## where R is analkyl group of from 1 to 16 carbon atoms, benzyl or phenyl.
 2. Acompound according to claim 1 where R is an alkyl group.
 3. A compoundaccording to claim 1 where R is phenyl.
 4. A compound according to claim1 where R is benzyl.
 5. A compound according to claim 1 where R isdodecyl.
 6. A compound according to claim 1 where R is N-propyl.
 7. Acompound according to claim 1 where R is isopropyl.
 8. A composition forinhibiting growth of bacteria and fungi on agriculturally desirableplants and crops comprising a microbiologically effective amount of acompound of the formula: ##STR5## where R is an alkyl group of from 1 to16 carbon atoms, benzyl, or phenyl and an inert carrier.
 9. Acomposition according to claim 8 where R is alkyl.
 10. A compositionaccording to claim 8 where R is dodecyl.
 11. A process for preparingcompounds of the formula: ##STR6## where R is an alkyl group of from 1to 16 carbon atoms, benzyl or phenyl comprising reacting an amide of theformula: ##STR7## with at least one mole of a sulfur monohalide, S₂ X₂,where X is bromine or chlorine, at a temperature of from -10° to 60° C.for 10 to 18 hours.
 12. A method of preparing compounds of the formula:##STR8## where R is a hydrocarbon of from 1 to 16 carbon atomscomprising reacting a mole of a compound of the formula: ##STR9## withfrom 2 to 5 moles of sulfur monohalide.
 13. A compound according toclaim 11 where R is propyl.
 14. A compound according to claim 11 where Ris isopropyl.